Towards new therapeutic strategies in chondrosarcoma Schrage, Y.M.

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Schrage, Y.M.

Citation

Schrage, Y. M. (2009, November 5). Towards new therapeutic strategies in chondrosarcoma. Retrieved from https://hdl.handle.net/1887/14327

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/14327

Note: To cite this publication please use the final published version (if applicable).

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Contents

1.1 Chondrosarcoma

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<06FKUDJH-90*%RYpH3&:+RJHQGRRUQ 1.2 Clinical problems in chondrosarcoma management

+LVWRORJLFDOGLVWLQFWLRQEHWZHHQEHQLJQDQGORZJUDGH malignant cartilaginous tumours

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grading

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1.3 Exploring putative targets as alternatives to conventional anti- cancer therapy: aims and outline of the thesis

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peripheral tumours

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1.1 Chondrosarcoma 'HÀQLWLRQ

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from conventional central and peripheral chondrosarcoma constituting the ODUJHVWVXEJURXSaWKLVHQFRPSDVVHVUDUHVXEW\SHVVXFKDVFOHDUFHOO

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conventional chondrosarcoma.

Characteristics

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thought to arise from conventional chondrosarcoma in which tumour cells WUDQVGLIIHUHQWLDWHWRZDUGVDPRUHVSLQGOHFHOOSKHQRW\SH⁷. In addition, the UDUHVXEW\SHMX[WDFRUWLFDOFKRQGURVDUFRPDLVUHFRJQLVHGZKLFKDOVRFRQWDLQV

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Figure 1.1 Central chondrosarcoma$*URVVVSHFLPHQRIFHQWUDOFKRQGURVDUFRPDRIGLVWDO

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neoplasm, with an adverse prognosis. Diagnosis

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Therapy

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metastasize. Therefore, there is a trend in sarcoma centers to treat them E\ FXUHWWDJH ZLWK PDUJLQ LPSURYHPHQW E\ SKHQRO²³ RU FU\RVXUJHU\. In FRQWUDVWKLJKJUDGHWXPRXUVDUHXVXDOO\WUHDWHGE\RIWHQPXWLODWLQJZLGH

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Genetics

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1.2 Clinical problems in chondrosarcoma management ,QWKLVWKHVLVWKUHHFOLQLFDOSUREOHPVDUHDGGUHVVHG

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malignant cartilaginous tumours

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1.2.1 Histological distinction between benign and low-grade malignant cartilaginous tumours

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1.2.2 Lack of prognostic markers

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grade I chondrosarcoma almost never metastasise to distant organs, JUDGH ,, FKRQGURVDUFRPD PHWDVWDVLVHV LQ RI WKH FDVHV DQG JUDGH ,,,

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1.2.3 Challenges in chondrosarcoma treatment

Chondrosarcomas are notorious for their resistance to conventional chemo- DQG UDGLRWKHUDS\ OHDYLQJ VXUJHU\ WKH RQO\ WUHDWPHQW RSWLRQ 7KHUHIRUH

there is nothing with curative intention to offer to patients with tumours DW LQRSHUDEOH ORFDWLRQV RU PHWDVWDWLF GLVHDVH /LWWOH LV NQRZQ DERXW WKH

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fast dividing. Chondrosarcomas have a slow growth rate, as compared to other solid tumours, which suggests that chemotherapeutic agents PLJKW QRW EH ZRUNLQJ HIÀFLHQWO\ RQ WKH WXPRXU FHOOV 7KH WKLUG SUREOHP

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which prevents the formation of free radicals⁵⁰.

Treatment attempts using conventional treatment modalities

Treatment of conventional chondrosarcoma with conventional chemo- and

Enchondroma

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$W\SLDVHOGRPIRXQG Grade I

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Table 1.1 Histological criteria within the cartilaginous tumour spectrum Criteria are VLWHV\QGURPHDQGDJHGHSHQGHQW

(12)

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for recurrent disease, or for distant metastasis did not appear to alter the outcome.

New treatment attempts in radiotherapy

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Sensitisation for conventional treatment modalities

An important approach in overcoming resistance is to sensitise the FKRQGURVDUFRPDFHOOVWREHFRPHPRUHYXOQHUDEOHWRFRQYHQWLRQDOFKHPRRU

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in peripheral and high-grade central chondrosarcomas and is controlling FKRQGURF\WH SUROLIHUDWLRQ 2YHUH[SUHVVLRQ RI %&/ LQKLELWV DSRSWRVLV

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caused aggressiveness of chondrosarcoma cells in vitro⁵⁷ +RZHYHU RXU

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(13)

AimSubstanceDoseStudySubjects; base line characteristicsResponse*Median follow up Chemotherapy

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,9'D\ PJ m²*HP'D\PJ 2m doc

Phase I&66'SDn/a Trofosfamide2UDOPJGDLO\Phase II

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FKRQGURVDUFRPD progressiveness

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Phase I n/aVDUFRPDVSD in 2 sarcomasGD\V Table 1.2 Overview of clinical investigations on chondrosarcoma (CS) treatment 7KHEHVWRYHUDOOWXPRUUHVSRQVHZDVFDWHJRUL]HGE\XVLQJWKH 5HVSRQVH(YDOXDWLRQ&ULWHULDLQ6ROLG7XPRUV5(&,67IURPWKH1&, PD progressive disease, SD stable disease, PR partial remission, CR complete remission. Nd not documented.

(14)

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and metalloproteinases and cathepsin B suggesting a potential role for FDWKHSVLQLQKLELWRUV$QRWKHUWDUJHWIRUFKRQGURVDUFRPDWKHUDS\PLJKWEH

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the formation of estrogen, is active in chondrosarcoma . Therefore the use RI DQWLHVWURJHQ WUHDWPHQW ZKLFK KDV EHHQ HVWDEOLVKHG LQ EUHDVW FDQFHU

might have a place in the treatment of chondrosarcoma. Antiangiogenic WKHUDS\FRPELQHGZLWKFKHPRWKHUDS\ZDVVKRZQWRLQGXFHDSRSWRVLVLQD

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(15)

Cate- gory Treatment (modality/ drug)Trial nameTumours enrolledCurrent statusPhaseExecuterNr of patientsStart 153URWRQEHDP

(YDOXDWLRQRI3URWRQ %HDP7KHUDS\IRU6NXOO Base Chondrosarcoma Skull Base Chondrosarcoma5Phase II 0'$QGHUVRQ Cancer Center

70Apr- 07 NT$SRPDE

(IÀFDF\DQG6DIHW\RI 6LQJOH$JHQW$SRPDELQ Patients With Advanced Chondrosarcoma

ChondrosarcomaCLPhase IIGenentech90Jun- 07 153URWRQEHDP

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&KRQGURVDUFRPDV of the Base of Skull

Skull Base Chondrosarcoma, Chordoma

5Phase II

8QLYHUVLW\RI Florida

Oct- NTPerifosineTrial of Perifosine in Patients With Chemo- Insensitive Sarcoma

Chondrosarcomas, Alveolar Soft Part 6DUFRPDV([WUD 6NHOHWDO0\[RLG Chondrosarcomas

$15Phase IIAOI Pharma, Inc.Nov- CC

3HPHWUH[HG disodium 3HPHWUH[HGIRU$GYDQFHG Chondrosarcomas

Chondrosarcoma$15Phase IINCI75Sep- 05 CC

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*HPFLWDELQH K\GURFKORULGHDQG GRFHWD[HOLQWUHDWLQJ patients with recurrent RVWHRVDUFRPD(ZLQJ·V VDUFRPDRUXQUHVHFWDEOH RUORFDOO\UHFXUUHQW chondrosarcoma (ZLQJ·V6DUFRPD Osteosarcoma, 8QUHVHFWDEOH2U /RFDOO\5HFXUUHQW Chondrosarcoma

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&KDUJHG3DUWLFOH57 for Chordomas and Chondrosarcomas of the Base of Skull or Cervical spine

Chordomas and Chondrosarcomas of the Base of Skull or Cervical spine

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Table 1.3 Current clinical trials in which chondrosarcoma patients are enrolled 6RXUFHKWWSFOLQLFDOUHVHDUFKQLKJRY&DWHJRU\&5 &RQYHQWLRQDOUDGLDWLRQ151HZUDGLDWLRQPRGDOLW\&&&RQYHQWLRQDOFKHPRWKHUDSHXWLFV171HZWKHUDSHXWLFWDUJHWV&XUUHQWVWDWXV55HFUXLWLQJ $15$FWLYHQRWUHFUXLWLQJ&&RPSOHWHG&/FORVHGIRUFKRQGURVDUFRPDV

(16)

1.3 Finding alternatives to conventional anti-cancer therapy in chondrosarcoma: aim and outline of the thesis

Before addressing the approaches to new therapeutic treatment of FKRQGURVDUFRPDWKDWDUHSUHVHQWHGLQWKLVWKHVLVWKHVRPHWLPHVSUREOHPDWLF

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tumours.

Four different approaches to new therapeutic treatment of chondrosarcoma are presented in this thesis.

1.3.1 Normal growth regulators (Morphogens/HSPGs) in analogy to peripheral tumours

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central chondrosarcomas.

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normal growth process might elucidate the development of cartilaginous WXPRXUV7KHJURZWKSODWHLVDFDUWLODJLQRXVVWUXFWXUHHQWUDSSHGEHWZHHQ

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(17)

AimSubstanceActionIn vitro/ in vivoSubjectsResponse Sensitizing to chemotherapy%,%5

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In vitro

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References

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